Despite the development of potent anti-retroviral therapy (ART) that effectively suppresses virus replication in the majority of HIV-infected individuals, a treatment capable of curing this infection is still not available. Residual disease in ART-treated, HIV-infected individuals consists mainly of (i) persistent inflammation, limited CD4+ T cell reconstitution, and premature immune senescence, and (ii) the presence of persistent reservoirs of latently infected cells that are not affected by ART and are responsible for the rapid rebound of virus replication if ART is interrupted. Gut is the first major site where HIV infection and replication takes place, with CD4+ T cells that express the co-receptor CCR5 and the heterodimeric gastrointestinal tissue (GIT) homing molecule ?4?7 integrin serving as the major target. Indeed, HIV infection is associated with a profound loss of mucosal immunological and physical integrity, which is considered a key cause of inflammation during HIV infection. Importantly, inflammation may critically contribute to HIV persistence by several mechanisms: driving the infection of susceptible cells that sustain the persistence of the reservoir; up-regulating the expression of co-inhibitory receptors, which contribute to the persistence of latently infected cells; and limiting the function of HIV-specific immune responses that could potentially clear the virus. Therefore, developing strategies aimed at limiting inflammation and improving immune responses especially in the gut and other lymphoid tissues may critically impact on HIV persistence, and is a key priority for HIV research. The overarching goal of this project is to explore the therapeutic potential of a novel, combined Interleukin (IL)-21 and anti-?4?7 intervention in ART-treated, SIV-infected rhesus macaques (RMs). Based on an exciting set of data we recently generated in separate studies that utilized IL-21 or anti-?4B7 interventions alone, we propose that IL- 21 supplementation of anti-?4?7 treatment will result in reduced immune dysfunction and inflammation (via IL-21) as well as in protection of gut from SIV infection and virologic control (via anti-?4?7). As such, we hypothesize that by targeting key contributors of HIV persistence, IL-21 supplementation of anti-?4?7 treatment will have a strong synergistic effect in the progressive reduction and potential elimination of the HIV reservoir. We are confident the proposed studies will provide in vivo evidence of reduced establishment (Aim 1) and maintenance (Aim 2) of the viral reservoir following combined IL-21 and anti-?4?7 treatment. This study will be conducted in the most relevant preclinical animal model of HIV infection and using two molecules that, as a single agent, are being tested for cancer (IL-21) or approved by the FDA for treatment of IBD and colitis (anti- ?4?7). Moreover, we are proposing a series of mechanistic studies aimed at defining the molecular and cellular effects of the proposed intervention. If successful, the proposed immune-based intervention would inform human clinical trials aimed at functionally curing HIV infection. Thus, we believe that the proposed studies are of high and immediate significance to the field of HIV cure research.